Victoria Kugel
Chem 367
Drexel University Department of Chemistry
Drexel University, Philadelphia, PA 19104
Submitted December 6, 2011
Melanoma is a dangerous form of skin cancer that evolves from melanocytes [1]. Until recently, the only cure for this cancer was a drug called dacarbazine. Dacarbazine has an average response rate of about 7-12% [2]. In August of 2011, a new drug called Vemurafenib was approved for the treatment of metastatic melanoma. Vemurafenib works by inhibiting the BRAF V600E mutation, which blocks the uncontrollable proliferation of cells [3]. In the phase three trials of vemurafenib, it was found that this drug reduced the risk of death by 63% [4]. Some adverse effects of this drug have been noticed, including rash, photosensitivity, pruritus, skin papilloma, alopecia, and dry skin [5]. Taking into account these non-life threatening side effects that sometimes arise with the treatment of vemurafenib, this new drug has brought about a huge advance in the treatment of metastatic melanoma.
Introduction
The most dangerous type of skin cancer is melanoma. Melanoma evolves from melanocytes, which are normal pigment cells [1]. Melanocytes are found in the lowest part of the epidermis. The epidermis is the outermost layer of the skin; right below the epidermis is the dermis. Melanocytes are responsible for making melanin, which is the pigment that gives skin color. The formation of a mole occurs when a group of melanocytes grow together. Although this is normal, it can become dangerous when the melanocytes start to change and proliferate uncontrollably. Melanoma can form in these moles that were previously cancer free, or it can also form on an area of skin that appears normal [6]. If these cells start to grow uncontrollably (which all cells in the body could potentially do), it results in this dangerous cancer [1]. Cutaneous malignant melanoma has an extremely high morbidity rate; it is responsible for 65% of all deaths due to skin cancer [7]. The average survival time of patients with this cancer is 6-10 months [8]. The most common factor that leads to melanoma is exposure to UV light, which can occur from either the sun or tanning beds. Although not every case of this cancer has symptoms, there is a way to check to see if you are at risk, called the ABCDE mnemonic. Each letter stands for a symptom that could indicate melanoma [1]. Below in figure 1 is an image where each letter in the mnemonic is defined.
Figure 1: Image defining each letter in the ABCDE mnemonic, with a picture corresponding to each one [1].
BRAF
There are a number of mutations that are expressed in cutaneous melanoma. Even though there are thousands of mutations that exist, there is one specific mutation that occurs most often, called the BRAF V600E mutation [9]. The BRAF mutation is expressed in more than half of all melanomas that develop. [10]. BRAF comes from a group of protein kinases called RAF. The RAF group of protein kinases participates in the mitogen-activated protein kinase pathway as signaling molecules. BRAF is a protein kinase specific to serine/threonine. When activated, BRAF moves to the cell membrane where it undergoes a series of reactions that result in a signaling cascade. The signals given off are for growth, which are very important in helping the cell grow, proliferate, and survive. When the BRAF is mutated, certain steps in the signaling cascade are avoided. This results in unregulated signals, which cause an excessive amount of cell proliferation [9]. Out of all of the BRAF mutations, more than 90% are the specific mutation BRAF V600E [10]. In the mutated BRAF V600E, valine is replaced with glutamic acid at the 600th amino acid position in the protein kinase [9].
Detecting Mutated BRAF
There are a number of ways to detect if the BRAF mutation is expressed in the melanoma. One method is called Sanger sequencing. This method amplifies the DNA segment and cuts off the segment at a random length. If the BRAF is unmutated, a primer extension will be at the end of the DNA segment. If the BRAF is mutated, the primer extension will be cut off before the end. This is how they distinguish if the melanoma contains the BRAF mutation [11].
Another way to detect if the BRAF mutation is expressed in the melanoma is through a method called pyrosequencing. Pyrosequencing is based on the sequencing-by-synthesis principle, and is a form of DNA sequencing technology [12]. After the released pyrophosphate from the DNA polymerase combines with the adenosine 5’ phosphate to make adenosine triphosphate, a visible light is given off. This light is due to the oxyluciferin that was made from the addition of luciferase. The light is only detected by the instrument when a base is incorporated. Since the DNA nucleotides have a predetermined order, a technologist can tell if the mutation is there or not by putting back together the sequence of bases that was created [11].
A third way to detect mutated BRAF is through a test called Cobas 4800 BRAFV600 Mutation Test. Different fluorescent dyes are directed at mutated and unmutated BRAF 600 genes. The characteristic fluorescence is measured. This measurement can determine whether or not the BRAF V600E mutation is present [11].
Vemurafenib
The signaling pathway that the RAF protein kinases are a part of is extremely important for how cells respond to growth signals. A study in 2002 showed that when a mutation was put into the BRAF gene, it led to melanoma. Knowing both of these things, it was realized that a small molecule that inhibits the BRAF V600E gene could possibly be synthesized as an anticancer drug. This drug was eventually synthesized, and is called vemurafenib. Vemurafenib is an inhibitor of the BRAF kinase. It was approved by the US Food and Drug Administration in August 2011 [3]. This drug is available as oral tablets that contain 240mg each. The dosage of vemurafenib is 960mg a day; therefore two tablets are taken twice a day with a glass of water. Food may or may not accompany the dose, however it is recommended to stick to one procedure (either taking it with food always or always without). If a patient misses a dose, he/she has up to four hours before the next dose to take the one that was missed. Vemurafenib has the potential to affect other prescribed drugs that the patient may be taking like contraceptive pills or anti-infectives. Therefore, it is imperative for the patient’s doctor to know all medication that is being consumed to prevent these types of mishaps [13].
Phase One Trials
In the phase one trials of vemurafenib, the group of patients that participated all had tumors that were not affected by the standard therapy available. These patients were all given a life expectancy of three months to live. The way this trial worked was each patient was given a 160mg dose of vemurafenib, twice a day. If after four weeks the patient did not experience any adverse effects, the dose was increased. This procedure went on as the dose of vemurafenib was increased from 160mg, to 240mg, then 320 or 360mg, up to 720mg, and ending with 1120mg taken orally twice daily. From the results of this escalating dose trial, they planned to find the dose that worked best with patients, and use that in the phase two trials. The way they determined which dose to use was by a ratio. The highest dose that caused no more than 1 out of every 6 people adverse effects was the dose chosen for use in the phase two trials. This dose was found to be 960mg taken twice daily [4].
Phase Two Trials
In the phase two trials, 132 patients participated. The overall response rate for all 132 patients was 52.3%. With the goal for the response rate at 30%, this trial turned out to be a success. The average time period of progression-free survival was a little over 6 months. Although some adverse effects were experienced, none of the effects were very serious. Some of the adverse effects included rash, photosensitivity, and fatigue [4].
Phase Three Trials
The purpose of the phase three trials was to compare the effectiveness of vemurafenib with dacarbazine [4]. Dacarbazine is an anticancer drug used to treat metastatic melanoma that was approved in the 1970s [14]. Prior to vemurafenib, dacarbazine was only drug approved by the FDA for the treatment of metastatic melanoma. Since this drug has an average response rate of only 7 to 12%
[2], it is understandable why a new anticancer drug for the treatment of melanoma needed to be developed. 675 people participated in these phase three trials from over 100 sites around the world. All patients had either stage IIIC or stage IV melanoma, tested positive for the specific BRAF V600E mutation, and had not been treated in the past. From a random drawing, half of the patients were chosen to receive 960mg of vemurafenib twice daily orally, while the other half was chosen to receive 1000 mg/m2 of dacarbazine by injection every three weeks. In the patients treated with vemurafenib, it was found that the risk of death was reduced by 63%. The percentage of people in the vemurafenib group that had a 6-month overall survival was 84%, compared to only 64% for people in the dacarbazine group. The vemurafenib was found to reduce the risk of the tumor progressing by 74%. In the dacarbazine group, only about 5% of the people had a partial response to the drug. There were very few people in this group who even had a noticeable decrease in the size of their tumor. Therefore, there was a significant different in the overall response of each group, which heavily favored the vemurafenib drug over the dacarbazine [4]. Below in figure 2 is an image with some more statistics from the trials, comparing vemurafenib with dacarbazine.
Figure 2: statistics from the phase three trials, broken down into subgroups for example age, gender, and region. The chart also seperates the patients in the vemurafenib group from the patients in the dacarbazine group [2].
Adverse Effects to Vemurafenib
From all three phases of clinical trials that were performed, a number of cutaneous adverse effects appeared on some of the patients that participated in these trials. The reason for these adverse effects is not clear, however it is speculated that they are due to either the changes in the signaling pathway that the vemurafenib makes, or the predisposition to skin conditions that the patients with melanoma might have. Since the adverse effects that appear with the drug vemurafenib are very similar to the adverse effects that appear with the drug sorafenib, this suggests that the blocking of the BRAF pathway (which both drugs are synthesized to do) may be the culprit to some of these symptoms [15]. Some of the most common adverse effects experienced by the patients that participated in the clinical trials are rash, photosensitivity, pruritus, skin papilloma, alopecia, and dry skin. Cutaneous SCC/keratoacanthoma, Palmar-plantar erythrodysaesthesia and erythema nodosum-like panniculitis are some of the less common side effects that patients taking vemurafenib experienced. Now that the treatment has been on the market for some time, more adverse effects are starting to appear that may not have been reported in the trials; an example of this is panniculitis [5]. Some other examples include benign epithelial entities like hand-foot skin reaction and prominent follicular cystic plugging [16]. More detailed information about some of the adverse effects is listed below.
Rash
During the phase one trials, 68% of the patients participating in the trial experienced rashes. This percentage was decreased to 52% in the phase two trials, and down to 36% in phase three. All of the patients experienced folliculocentric rashes, however in some cases the rashes came together to form a harmful erythema-like eruption. In the image below, figure 3 shows an example of folliculocentric rashes, and figure 4 shows an example of the erythema-like eruption on a patient’s back.
Figure 3: Folliculocentric rashes present on a patients leg[5].
Figure 4: Erythema-like eruptions present on a patient’s back[5].
The folliculocentric rash appeared as red bumps, most often found on the limbs, back, and abdomen, however never on the face. The erythema-like eruption that formed in some cases resembled a similar eruption that forms on the skin which is associated with drug use. While in some cases this only caused itching for the patients, some experienced a fever. One patient was hospitalized due to the fever and confused state that was caused by the rash [5]
Photosensitivity
The percentage of patients who experienced photosensitivity in the phase one trials was 42%. In phase two, this number was increased to 52%, and then decreased to 30% in phase three. The most common areas that this photosensitivity affected were the chest, back of the hands, and toes. These are areas that are most likely to receive sunlight when going outdoors. The onset of this symptom usually occurred within 24 hours of sun exposure. Since a patient reported to have received photosensitivity while indoors sitting next to a window, it is speculated that UV light is responsible for causing the irritation since UV light is capable of passing though glazing. This speculation was later confirmed by a study that proved this theory [5]. The severity of the photosensitivity can vary. It was documented that one patient received blistering reactions due to the extreme photosensitivity they experienced [17].
Squamoproliferative Eruptions
A side effect of vemurafenib that can be more serious is squamoproliferative eruptions. These eruptions can be in the form of harmless skin tags, but can range all the way to squamous cell carcinoma. The percentage of patients who experienced harmless skin tags in phase two and three trials ranged from 18 to 29%. The percentage of patients who experienced squamous cell carcinoma in the second and third phase trials ranged from 8 to 12%. For those patients who did develop squamous cell carcinoma during treatment, it appeared around 7-8 weeks after starting treatment. Below in figure 5 is an image of squamous cell carcinoma on a patient’s arm [5].
Figure 5: An example of squamous cell carcinoma on a patient’s arm [5].
Panniculitis
Although not reported in the clinical trials, there were a few patients who experienced erythema nodosum like panniculitis [5]. Panniculitis is the inflammation of adipose tissue. Most associate adipose tissue with the storing and releasing of fats, however it also plays a keen role in inflammation and immunity [18]. Panniculitis belongs to a heterogeneous group of disorders called panniculitides. Most often, nodules on the lower limbs appear from this disorder; however these nodules may or may not be painful. Clinical diagnosis of this disorder is difficult due to the evolution of the panniculitis over time. Erythema nodosum panniculitis, the type that sometimes appears as an adverse effect to vemurafenib, falls under the category of septal panniculitis without vasculitis. This is the most common type of panniculitis. Appearing 3-6 times more in females, this disorder appears as a symmetric lesion, changing color over time. Starting out as a red color, over time it progresses to a purple hue, then to a green/ yellow color which can look like a bruise. Below in figure 6 is a picture of erythema nodosum panniculitis on a patient’s legs [19].
Figure 6: An example of erythema nodosum panniculitis on a patient’s legs [19].
Hand Foot Skin Reaction (HFSR)
Hand foot skin reaction is a term used under the group of syndromes called hand foot syndrome. HFSR specifically refers to the hand foot syndrome that occurs in patients that are using drugs that fall into the class of multiple tyrosine kinase inhibitors. Due to the unique signs and symptoms of patients taking drugs in this class, the reaction has termed its own name. The first sign of HFSR is a strange, tingling feeling on the palms of the hands and soles of the feet. This tingling usually progresses to a burning pain over the course of several days. Dry skin, which appears as white scales, then starts to arise. This symptom is usually more noticeable on the hands and fingers than on the soles of the feet. It was reported that HFSR, unlike other forms of hand foot syndrome that do not arise in response to multiple tyrosine kinase inhibitors, produces these patches of dry skin not only in areas of the hands and feet that receive the most pressure, but also on areas that rub against neighboring surfaces. Below in figure 7 is an example of HFSR on a patient’s foot. This patient is receiving a multiple tyrosine kinase inhibitor called sorafenib [20].
Figure 7: Hand foot skin reaction on a patient’s foot due to a side effect from the drug sorafenib that this patient is currently taking [20].
Conclusion
Melanoma is a dangerous form of skin cancer that evolves from melanocytes [1]. Dacarbazine is an anticancer drug used to treat metastatic melanoma that was approved by the FDA in the 1970s [14]. Dacarbazine has an overall response rate of 7-12%. Until recently, this was the only option for those suffering from metastatic melanoma [2]. In August of 2011, a new drug called Vemurafenib was approved by the FDA for the treatment of metastatic melanoma. Vemurafenib works by inhibiting the BRAF V600E mutation, which blocks the uncontrollable proliferation of cells [3]. BRAF is a gene that, upon activation, moves to the cell membrane where it undergoes a series of reactions that ultimately lead to sending off growth signals to the cell. When the BRAF gene is mutated, unregulated signals are sent out and cause an excessive amount of cell proliferation [9]. In the phase three trials of vemurafenib, it was found that this drug reduced the risk of death by 63%. Only about 5% of the patients in the dacarbazine group even had a noticeable reduction in the size of their tumor [4]. Some adverse effects of this drug have been noticed, including rash, photosensitivity, pruritus, skin papilloma, alopecia, and dry skin. Erythema nodosum panniculitis was also noted in a few patients; however this symptom was not reported in the clinical trials [5]. Taking into account these non-life threatening side effects that sometimes arise with the treatment of vemurafenib, this new drug has still brought about a huge advance in the treatment of metastatic melanoma.
Works Cited
1. Pluta R. Melanoma. JAMA : the journal of the American Medical Association. 2011 -06-08;305(22):2368-. [DOI]
2. Chapman P, Hauschild A, Robert C, Haanen J, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day S, Sosman J, Kirkwood J, Eggermont A, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee R, Flaherty K, McArthur G. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30, 2011;364(26):2507-16. [DOI]
3. Flaherty K, Yasothan U, Kirkpatrick P. Vemurafenib. Nature Reviews.Drug Discovery. 2011 Nov 2011;10(11):811-2. [DOI]
4. Heakal Y, Kester M, Savage S. Vemurafenib (PLX4032): An orally available inhibitor of mutated BRAF for the treatment of metastatic melanoma. Ann Pharmacother. 2011 Nov;45(11):1399-405. [DOI]
5. Sinha R, Edmonds K, Newton-Bishop J, Gore M, Larkin J, Fearfield L. Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: Practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br J Dermatol. 2012;167(5):987-94. [DOI]
6. Plester G. Malignant melanoma. Practice Nurse. 2008 Jul 11, 2008;36(1):22-8. [DOI]
7. Cummins D, Cummins J, Hardin P, Silverman M, Leonard A, Chanmugam A. Cutaneous malignant melanoma. Mayo Clin Proc. 2006 Apr 2006;81(4):500-7. [DOI]
8. Sosman J, Kim K, Schuchter L, Gonzalez R, Pavlick A, Weber J, McArthur G, Hutson T, Moschos S, Flaherty K, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis K, Amaravadi R, Chmielowski B, Lawrence H, Shyr Y, Ye F, Li J, Nolop K, Lee R, Joe A, Ribas A. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012 Feb 23, 2012;366(8):707-14. [DOI]
9. Ravnan M, Matalka M. Vemurafenib in patients with BRAF V600E mutation-positive advanced melanoma. Clin Ther. 2012 Jul 2012;34(7):1474-86. [DOI]
10. Ascierto P. The role of BRAF V600 mutation in melanoma. Journal of translational medicine. 2012;10(1):85. [DOI]
11. Curry J, Torres-Cabala C, Tetzlaff M, Bowman C, Prieto V. Molecular platforms utilized to detect BRAF V600E mutation in melanoma. Semin Cutaneous Med Surg. 2012;31(4):267-73. [DOI]
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14. Eggermont A, Kirkwood J. Re-evaluating the role of dacarbazine in metastatic melanoma: What have we learned in 30 years? Eur J Cancer. 2004 8;40(12):1825-36. [DOI]
15. Huang V. Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Archives of dermatology (1960). 2012 -05-01;148(5):628. [DOI]
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17. Chu E, Wanat K, Miller C, Amaravadi R, Fecher L, Brose M, McGettigan S, Giles L, Schuchter L, Seykora J, Rosenbach M. Diverse cutaneous side effects associated with BRAF inhibitor therapy: A clinicopathologic study. J Am Acad Dermatol. 2012;67(6):1265-72. [DOI]
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Vemurafenib: A New Hope for Metastatic Melanoma
Victoria KugelChem 367
Drexel University Department of Chemistry
Drexel University, Philadelphia, PA 19104
Submitted December 6, 2011
Melanoma is a dangerous form of skin cancer that evolves from melanocytes [1]. Until recently, the only cure for this cancer was a drug called dacarbazine. Dacarbazine has an average response rate of about 7-12% [2]. In August of 2011, a new drug called Vemurafenib was approved for the treatment of metastatic melanoma. Vemurafenib works by inhibiting the BRAF V600E mutation, which blocks the uncontrollable proliferation of cells [3]. In the phase three trials of vemurafenib, it was found that this drug reduced the risk of death by 63% [4]. Some adverse effects of this drug have been noticed, including rash, photosensitivity, pruritus, skin papilloma, alopecia, and dry skin [5]. Taking into account these non-life threatening side effects that sometimes arise with the treatment of vemurafenib, this new drug has brought about a huge advance in the treatment of metastatic melanoma.
Introduction
The most dangerous type of skin cancer is melanoma. Melanoma evolves from melanocytes, which are normal pigment cells [1]. Melanocytes are found in the lowest part of the epidermis. The epidermis is the outermost layer of the skin; right below the epidermis is the dermis. Melanocytes are responsible for making melanin, which is the pigment that gives skin color. The formation of a mole occurs when a group of melanocytes grow together. Although this is normal, it can become dangerous when the melanocytes start to change and proliferate uncontrollably. Melanoma can form in these moles that were previously cancer free, or it can also form on an area of skin that appears normal [6]. If these cells start to grow uncontrollably (which all cells in the body could potentially do), it results in this dangerous cancer [1]. Cutaneous malignant melanoma has an extremely high morbidity rate; it is responsible for 65% of all deaths due to skin cancer [7]. The average survival time of patients with this cancer is 6-10 months [8]. The most common factor that leads to melanoma is exposure to UV light, which can occur from either the sun or tanning beds. Although not every case of this cancer has symptoms, there is a way to check to see if you are at risk, called the ABCDE mnemonic. Each letter stands for a symptom that could indicate melanoma [1]. Below in figure 1 is an image where each letter in the mnemonic is defined.Figure 1: Image defining each letter in the ABCDE mnemonic, with a picture corresponding to each one [1].
BRAF
There are a number of mutations that are expressed in cutaneous melanoma. Even though there are thousands of mutations that exist, there is one specific mutation that occurs most often, called the BRAF V600E mutation [9]. The BRAF mutation is expressed in more than half of all melanomas that develop. [10]. BRAF comes from a group of protein kinases called RAF. The RAF group of protein kinases participates in the mitogen-activated protein kinase pathway as signaling molecules. BRAF is a protein kinase specific to serine/threonine. When activated, BRAF moves to the cell membrane where it undergoes a series of reactions that result in a signaling cascade. The signals given off are for growth, which are very important in helping the cell grow, proliferate, and survive. When the BRAF is mutated, certain steps in the signaling cascade are avoided. This results in unregulated signals, which cause an excessive amount of cell proliferation [9]. Out of all of the BRAF mutations, more than 90% are the specific mutation BRAF V600E [10]. In the mutated BRAF V600E, valine is replaced with glutamic acid at the 600th amino acid position in the protein kinase [9].Detecting Mutated BRAF
There are a number of ways to detect if the BRAF mutation is expressed in the melanoma. One method is called Sanger sequencing. This method amplifies the DNA segment and cuts off the segment at a random length. If the BRAF is unmutated, a primer extension will be at the end of the DNA segment. If the BRAF is mutated, the primer extension will be cut off before the end. This is how they distinguish if the melanoma contains the BRAF mutation [11].Another way to detect if the BRAF mutation is expressed in the melanoma is through a method called pyrosequencing. Pyrosequencing is based on the sequencing-by-synthesis principle, and is a form of DNA sequencing technology [12]. After the released pyrophosphate from the DNA polymerase combines with the adenosine 5’ phosphate to make adenosine triphosphate, a visible light is given off. This light is due to the oxyluciferin that was made from the addition of luciferase. The light is only detected by the instrument when a base is incorporated. Since the DNA nucleotides have a predetermined order, a technologist can tell if the mutation is there or not by putting back together the sequence of bases that was created [11].
A third way to detect mutated BRAF is through a test called Cobas 4800 BRAFV600 Mutation Test. Different fluorescent dyes are directed at mutated and unmutated BRAF 600 genes. The characteristic fluorescence is measured. This measurement can determine whether or not the BRAF V600E mutation is present [11].
Vemurafenib
The signaling pathway that the RAF protein kinases are a part of is extremely important for how cells respond to growth signals. A study in 2002 showed that when a mutation was put into the BRAF gene, it led to melanoma. Knowing both of these things, it was realized that a small molecule that inhibits the BRAF V600E gene could possibly be synthesized as an anticancer drug. This drug was eventually synthesized, and is called vemurafenib. Vemurafenib is an inhibitor of the BRAF kinase. It was approved by the US Food and Drug Administration in August 2011 [3]. This drug is available as oral tablets that contain 240mg each. The dosage of vemurafenib is 960mg a day; therefore two tablets are taken twice a day with a glass of water. Food may or may not accompany the dose, however it is recommended to stick to one procedure (either taking it with food always or always without). If a patient misses a dose, he/she has up to four hours before the next dose to take the one that was missed. Vemurafenib has the potential to affect other prescribed drugs that the patient may be taking like contraceptive pills or anti-infectives. Therefore, it is imperative for the patient’s doctor to know all medication that is being consumed to prevent these types of mishaps [13].Phase One Trials
In the phase one trials of vemurafenib, the group of patients that participated all had tumors that were not affected by the standard therapy available. These patients were all given a life expectancy of three months to live. The way this trial worked was each patient was given a 160mg dose of vemurafenib, twice a day. If after four weeks the patient did not experience any adverse effects, the dose was increased. This procedure went on as the dose of vemurafenib was increased from 160mg, to 240mg, then 320 or 360mg, up to 720mg, and ending with 1120mg taken orally twice daily. From the results of this escalating dose trial, they planned to find the dose that worked best with patients, and use that in the phase two trials. The way they determined which dose to use was by a ratio. The highest dose that caused no more than 1 out of every 6 people adverse effects was the dose chosen for use in the phase two trials. This dose was found to be 960mg taken twice daily [4].Phase Two Trials
In the phase two trials, 132 patients participated. The overall response rate for all 132 patients was 52.3%. With the goal for the response rate at 30%, this trial turned out to be a success. The average time period of progression-free survival was a little over 6 months. Although some adverse effects were experienced, none of the effects were very serious. Some of the adverse effects included rash, photosensitivity, and fatigue [4].Phase Three Trials
The purpose of the phase three trials was to compare the effectiveness of vemurafenib with dacarbazine [4]. Dacarbazine is an anticancer drug used to treat metastatic melanoma that was approved in the 1970s [14]. Prior to vemurafenib, dacarbazine was only drug approved by the FDA for the treatment of metastatic melanoma. Since this drug has an average response rate of only 7 to 12%[2], it is understandable why a new anticancer drug for the treatment of melanoma needed to be developed. 675 people participated in these phase three trials from over 100 sites around the world. All patients had either stage IIIC or stage IV melanoma, tested positive for the specific BRAF V600E mutation, and had not been treated in the past. From a random drawing, half of the patients were chosen to receive 960mg of vemurafenib twice daily orally, while the other half was chosen to receive 1000 mg/m2 of dacarbazine by injection every three weeks. In the patients treated with vemurafenib, it was found that the risk of death was reduced by 63%. The percentage of people in the vemurafenib group that had a 6-month overall survival was 84%, compared to only 64% for people in the dacarbazine group. The vemurafenib was found to reduce the risk of the tumor progressing by 74%. In the dacarbazine group, only about 5% of the people had a partial response to the drug. There were very few people in this group who even had a noticeable decrease in the size of their tumor. Therefore, there was a significant different in the overall response of each group, which heavily favored the vemurafenib drug over the dacarbazine [4]. Below in figure 2 is an image with some more statistics from the trials, comparing vemurafenib with dacarbazine.
Figure 2: statistics from the phase three trials, broken down into subgroups for example age, gender, and region. The chart also seperates the patients in the vemurafenib group from the patients in the dacarbazine group [2].
Adverse Effects to Vemurafenib
From all three phases of clinical trials that were performed, a number of cutaneous adverse effects appeared on some of the patients that participated in these trials. The reason for these adverse effects is not clear, however it is speculated that they are due to either the changes in the signaling pathway that the vemurafenib makes, or the predisposition to skin conditions that the patients with melanoma might have. Since the adverse effects that appear with the drug vemurafenib are very similar to the adverse effects that appear with the drug sorafenib, this suggests that the blocking of the BRAF pathway (which both drugs are synthesized to do) may be the culprit to some of these symptoms [15]. Some of the most common adverse effects experienced by the patients that participated in the clinical trials are rash, photosensitivity, pruritus, skin papilloma, alopecia, and dry skin. Cutaneous SCC/keratoacanthoma, Palmar-plantar erythrodysaesthesia and erythema nodosum-like panniculitis are some of the less common side effects that patients taking vemurafenib experienced. Now that the treatment has been on the market for some time, more adverse effects are starting to appear that may not have been reported in the trials; an example of this is panniculitis [5]. Some other examples include benign epithelial entities like hand-foot skin reaction and prominent follicular cystic plugging [16]. More detailed information about some of the adverse effects is listed below.Rash
During the phase one trials, 68% of the patients participating in the trial experienced rashes. This percentage was decreased to 52% in the phase two trials, and down to 36% in phase three. All of the patients experienced folliculocentric rashes, however in some cases the rashes came together to form a harmful erythema-like eruption. In the image below, figure 3 shows an example of folliculocentric rashes, and figure 4 shows an example of the erythema-like eruption on a patient’s back.Figure 3: Folliculocentric rashes present on a patients leg[5].
Figure 4: Erythema-like eruptions present on a patient’s back[5].
The folliculocentric rash appeared as red bumps, most often found on the limbs, back, and abdomen, however never on the face. The erythema-like eruption that formed in some cases resembled a similar eruption that forms on the skin which is associated with drug use. While in some cases this only caused itching for the patients, some experienced a fever. One patient was hospitalized due to the fever and confused state that was caused by the rash [5]
Photosensitivity
The percentage of patients who experienced photosensitivity in the phase one trials was 42%. In phase two, this number was increased to 52%, and then decreased to 30% in phase three. The most common areas that this photosensitivity affected were the chest, back of the hands, and toes. These are areas that are most likely to receive sunlight when going outdoors. The onset of this symptom usually occurred within 24 hours of sun exposure. Since a patient reported to have received photosensitivity while indoors sitting next to a window, it is speculated that UV light is responsible for causing the irritation since UV light is capable of passing though glazing. This speculation was later confirmed by a study that proved this theory [5]. The severity of the photosensitivity can vary. It was documented that one patient received blistering reactions due to the extreme photosensitivity they experienced [17].Squamoproliferative Eruptions
A side effect of vemurafenib that can be more serious is squamoproliferative eruptions. These eruptions can be in the form of harmless skin tags, but can range all the way to squamous cell carcinoma. The percentage of patients who experienced harmless skin tags in phase two and three trials ranged from 18 to 29%. The percentage of patients who experienced squamous cell carcinoma in the second and third phase trials ranged from 8 to 12%. For those patients who did develop squamous cell carcinoma during treatment, it appeared around 7-8 weeks after starting treatment. Below in figure 5 is an image of squamous cell carcinoma on a patient’s arm [5].Figure 5: An example of squamous cell carcinoma on a patient’s arm [5].
Panniculitis
Although not reported in the clinical trials, there were a few patients who experienced erythema nodosum like panniculitis [5]. Panniculitis is the inflammation of adipose tissue. Most associate adipose tissue with the storing and releasing of fats, however it also plays a keen role in inflammation and immunity [18]. Panniculitis belongs to a heterogeneous group of disorders called panniculitides. Most often, nodules on the lower limbs appear from this disorder; however these nodules may or may not be painful. Clinical diagnosis of this disorder is difficult due to the evolution of the panniculitis over time. Erythema nodosum panniculitis, the type that sometimes appears as an adverse effect to vemurafenib, falls under the category of septal panniculitis without vasculitis. This is the most common type of panniculitis. Appearing 3-6 times more in females, this disorder appears as a symmetric lesion, changing color over time. Starting out as a red color, over time it progresses to a purple hue, then to a green/ yellow color which can look like a bruise. Below in figure 6 is a picture of erythema nodosum panniculitis on a patient’s legs [19].Figure 6: An example of erythema nodosum panniculitis on a patient’s legs [19].
Hand Foot Skin Reaction (HFSR)
Hand foot skin reaction is a term used under the group of syndromes called hand foot syndrome. HFSR specifically refers to the hand foot syndrome that occurs in patients that are using drugs that fall into the class of multiple tyrosine kinase inhibitors. Due to the unique signs and symptoms of patients taking drugs in this class, the reaction has termed its own name. The first sign of HFSR is a strange, tingling feeling on the palms of the hands and soles of the feet. This tingling usually progresses to a burning pain over the course of several days. Dry skin, which appears as white scales, then starts to arise. This symptom is usually more noticeable on the hands and fingers than on the soles of the feet. It was reported that HFSR, unlike other forms of hand foot syndrome that do not arise in response to multiple tyrosine kinase inhibitors, produces these patches of dry skin not only in areas of the hands and feet that receive the most pressure, but also on areas that rub against neighboring surfaces. Below in figure 7 is an example of HFSR on a patient’s foot. This patient is receiving a multiple tyrosine kinase inhibitor called sorafenib [20].Figure 7: Hand foot skin reaction on a patient’s foot due to a side effect from the drug sorafenib that this patient is currently taking [20].
Conclusion
Melanoma is a dangerous form of skin cancer that evolves from melanocytes [1]. Dacarbazine is an anticancer drug used to treat metastatic melanoma that was approved by the FDA in the 1970s [14]. Dacarbazine has an overall response rate of 7-12%. Until recently, this was the only option for those suffering from metastatic melanoma [2]. In August of 2011, a new drug called Vemurafenib was approved by the FDA for the treatment of metastatic melanoma. Vemurafenib works by inhibiting the BRAF V600E mutation, which blocks the uncontrollable proliferation of cells [3]. BRAF is a gene that, upon activation, moves to the cell membrane where it undergoes a series of reactions that ultimately lead to sending off growth signals to the cell. When the BRAF gene is mutated, unregulated signals are sent out and cause an excessive amount of cell proliferation [9]. In the phase three trials of vemurafenib, it was found that this drug reduced the risk of death by 63%. Only about 5% of the patients in the dacarbazine group even had a noticeable reduction in the size of their tumor [4]. Some adverse effects of this drug have been noticed, including rash, photosensitivity, pruritus, skin papilloma, alopecia, and dry skin. Erythema nodosum panniculitis was also noted in a few patients; however this symptom was not reported in the clinical trials [5]. Taking into account these non-life threatening side effects that sometimes arise with the treatment of vemurafenib, this new drug has still brought about a huge advance in the treatment of metastatic melanoma.Works Cited
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